Abstract B086: Novel myeloid activation therapy promotes regression of metastatic ovarian cancer

Abstract

Abstract Significance: Most ovarian cancer (OC) patients ultimately succumb to drug-resistant intraperitoneal metastases. There is an unmet need to develop novel therapies against metastatic OC. Whether activating myeloid cells can promote OC regression has not been explored extensively. The purpose of this study is to develop a novel immunotherapy that activates myeloid cells with the goal of eradicating metastatic OC. Methods: In this study, we mainly relied on syngeneic mouse models of metastatic OC. To model metastatic OC in mice, we performed intraperitoneal injection of clinically relevant murine OC cell lines that were recently established by Dr. Robert Weinberg’s group, including homologous recombination (HR)-proficient KPCA cells (KRASG12VTrp53R172HCcne1OEAkt2OE ) and HR-deficient BPPNM cells (Brca1−/−Trp53R172HPten−/− Nf1−/−MycOE ). To activate myeloid cells, we used b-glucan and interferon (IFN) γ. b-glucan is a yeast cell wall polysaccharide that is currently in clinical trials to treat multiple cancers (NCT05159778). It canonically activates myeloid cells through the Dectin-1-spleen tyrosine kinase (SYK) pathway and induces infiltration of monocytes and neutrophils. IFNγ activates macrophages to an anti-tumor status. We investigated whether and how b-glucan affects metastatic OC with or without IFNγ using bioluminescence imaging, confocal imaging, flow cytometry, and single-cell RNA sequencing (scRNA seq). Finally, we tested whether combining myeloid cell activation with carboplatin could eradicate metastatic OC.Results: First, we found that b-glucan alone was highly efficient in clearing ascites. b-glucan captured free-floating OC cells into solid nodules within 5 hours after its injection through two non-redundant and equally important pathways: (1) an unexpected Dectin-1-SYK-independent, heparin-sensitive pathway that was mediated by resident macrophages in the peritoneal fluid; (2) a Dectin-1-SYK-PAD4-dependent pathway that was mediated by neutrophil extracellular traps in the omentum. Second, we found that combining b-glucan with IFNγ (b-glucan/IFNγ) not only cleared ascites but also reduced total metastases compared to PBS-, b-glucan-, or IFNγ-treated mice. This anti-tumor immunity required T cells and non-tumor IFNγ signaling in the host. Third, using scRNA seq, we found that b-glucan/IFNγ induced the enrichment of unique subsets of tumoricidal neutrophils and macrophages compared to other groups. Interestingly, the novel macrophage subset selectively expressed an interleukin (IL)-12 family cytokine, IL-27. We found that blocking IL-27 significantly impaired the anti-tumor response. Finally, combining b-glucan/IFNγ with carboplatin nearly eradicated chemoresistant KPCA tumors and chemosensitive BPPNM tumors. Patients with high expression of the genes identified in the novel myeloid cell subsets correlate with better overall survival. Conclusion: We have identified a novel combination therapy of myeloid activation and chemotherapy that could potentially transform treatments against metastatic OC. Citation Format: Brennah Murphy, Taito Miyamoto, Bryan Manning, Toshitha Kannan, Anastasia Ghilkovsky, Yulia Nefedova, Daniel Claiborne, Rugang Zhang, Andrew Kossenkov, Nan Zhang. Novel myeloid activation therapy promotes regression of metastatic ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B086.